It has been estimated that approximately 4% of the people in the world suffer from depression, which is not caused by any known underlying neurological disease. Depression affects people in all walks of society, from the very young to the very old. It often occurs without the presence of a precipitating event, and can be unresponsive to psychotherapy, environmental changes or to pharmacotherapy with the currently available medications.
When an individual is suffering from depression, he or she will usually be in a depressed mood, as well as experience a loss of interest or pleasure in all, or almost all, activities. These and associated symptoms last for a period of at least two weeks. The associated symptoms may include, but not be limited to, appetite disturbance, change in weight, sleep disturbance, psychomotor agitation or retardation, decreased energy, feelings of worthlessness or excessive or inappropriate guilt, difficulty thinking or concentrating, and recurrent thoughts of death or suicidal ideation or attempts. Further, a person suffering from depression can also experience fearfulness, anxiety, irritability, brooding or obsessive rumination, excessive concern with physical health, panic attacks, and phobias.
Of those having mental disorders, a correlation between allergic reactions, and particularly rhinitis, to mental disorders, including depression, has been reported. There has as yet, however, been no report of a physiological connection between allergies and mental disorders.
In fact, there does not appear be a direct physiological association between a depressive episode and allergic reactions. For example, while Bell et al. [Psychosom. Med. 52:517 (1990)] describe an interrelation between social anxiety, allergies and distressed affect, such as depression and anxiety, in some persons, the authors conclude that extreme shyness may only be a stable temperamental feature of a person who also has susceptibility to nasal allergies. Likewise, in a separate publication, Bell et al. [Psycother. Psychosom. 55:24 (1991)] report that affective manifestations lack a definitive relation to the duration or severity of allergic disorders.
Other publications reveal further complications in understanding the physiological relationship between allergies and mental disorders. It appears that the susceptibility to mental disorders can extend beyond the allergic sufferers themselves to their relatives. Kagan et al. [Psychosom. Med., 53:332 (1991)] describe temperament disorders in children suffering from hay fever. The authors report that first and second degree relatives of extremely shy children reveal a greater prevalence of hay fever and social anxiety.
Thus, while there are reports of a relationship between allergies and mental disorders, there is no definitive understanding of a physiological connection between these conditions. Without such an understanding, discovery of a method for alleviating mental disorders in those that suffer from them, or reducing the susceptibility of such individuals to mental disorder, can only be done empirically. On the other hand, there are methods for evaluating the functionality of a potential treatment for mental disorders.
Several lines of evidence suggest that an altered activity of brain serotonergic pathways is related to several neuropsychiatric disorders. For example, lower levels of 5-hydroxyindoleacetic (5-HIAA), the main metabolite of serotonin (5-HT) in the cerebrospinal fluid have been reported in clinical studies of aggression, depression, impulsive crime and alcoholism. Several important genes for normal brain serotonin function have been cloned, including tryptophan hydroxylase, the serotonin transporter, monoamine oxidases A and B and several serotonin receptors. In addition, serotonin receptor agonists and antagonists have been developed as drugs for treating specific neuropsychiatric disorders. Drugs with affinity for 5-HT.sub.2 receptors have been used to treat schizophrenia, Parkinsonism, and anxiety disorders. Several azapirones, such as buspirone, gepirone, and ipsapirone, have high affinities for 5HT.sub.1A receptors in the brain, and are used to treat anxiety. For example, clozapine which is an antipsychotic drug is used to treat schizophrenic patients who do not respond to other drug treatments. Clozapine has a strong affinity for the serotonin 5-HT.sub.2 subclass of receptors. In addition, 5-HT.sub.1A class agonists, such as buspirone, are effective treatments for anxiety. Highly selective 5-HT uptake inhibitors have been used successfully to treat depression.
Much recent interest in serotonin research has concentrated on the 5-HT.sub.7 receptor. This receptor and allelic variations of it are described in U.S. Pat. No. 5,763,183 as well as Shen et al, J. Biol. Chem. 268:18200 and Roth et al, J. Pharmacol Exp. Ther. 268:1403.
This receptor is a guanine nucleotide regulatory protein coupled receptor (GPCR) and, on the basis of its sequence, it is thought to have the typical GPCR structure of seven hydrophobic transmembrane helices separated by three extracellular and three intracellular loops. The 5-HT.sub.7 receptor has a distinct pharmacological profile which includes high affinity for clozapine and related atypical antipsychotic agents as well as for some typical antipsychotic agents.
Pharmacological studies in humans have also suggested that abnormal function of 5-HT.sub.7 receptors might play a role in the etiology of certain mental/social disorders. These disorders include, but are not limited to, depression, alcoholism, weight management disorders (loss/obesity), social disorder, impotence/sexual dysfunction, panic, obsessive/compulsive disorder. 5-HT.sub.7 is also present in vascular tissue and can be associated with vascular-associated conditions. These conditions include, but are not limited to, migraines, stroke, orthostatic hypotension, gastrointestinal stasis, nausea, dizziness and jet lag.
Accordingly, a chemical that interacts with this receptor could be a valuable drug.
It is clear that what is needed is a method of treating an at risk population to lessen their risk of mental disorder and depression and vascular diseases. Also needed is a method to treat those that suffer from these disorders to reduce their symptoms of mental disorder.